Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection

Yueh Ming Loo, David M. Owen, Kui Li, Andrea K. Erickson, Cynthia L. Johnson, Penny M. Fish, D. Spencer Carney, Ting Wang, Hisashi Ishida, Mitsutoshi Yoneyama, Takashi Fujita, Takeshi Saito, William M. Lee, Curt H. Hagedorn, Daryl T Y Lau, Steven A. Weinman, Stanley M. Lemon, Michael Gale

Research output: Contribution to journalArticle

320 Scopus citations

Abstract

Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-α/β response that limits virus infection. The hepatitis C virus (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls the host response to HCV is not known. Moreover, endogenous IPS-1 cleavage has not been demonstrated in the context of HCV infection in vitro or in vivo. Here, we show that HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation. This host response limits HCV production and constrains cellular permissiveness to infection. However, HCV disrupts this response early in infection by NS3/4A cleavage of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane. Cleavage results in subcellular redistribution of IPS-1 and loss of interaction with RIG-I, thereby preventing downstream activation of IRF-3 and IFN-β induction. Liver tissues from chronically infected patients similarly demonstrate subcellular redistribution of IPS-1 in infected hepatocytes and IPS-1 cleavage associated with a lack of ISG15 expression and conjugation of target proteins in vivo. Importantly, small-molecule inhibitors of NS3/4A prevent cleavage and restore RIG-I signaling of IFN-β induction. Our results suggest a dynamic model in which early activation of IRF-3 and induction of antiviral genes are reversed by IPS-1 proteolysis and abrogation of RIG-I signaling as NS3/4A accumulates in newly infected cells. HCV protease inhibitors effectively prevent IPS-1 proteolysis, suggesting they may be capable of restoring this innate host response in clinical practice.

Original languageEnglish (US)
Pages (from-to)6001-6006
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number15
DOIs
StatePublished - Apr 11 2006

Keywords

  • CARDIF
  • MAVS
  • VISA

ASJC Scopus subject areas

  • General

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    Loo, Y. M., Owen, D. M., Li, K., Erickson, A. K., Johnson, C. L., Fish, P. M., Carney, D. S., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Saito, T., Lee, W. M., Hagedorn, C. H., Lau, D. T. Y., Weinman, S. A., Lemon, S. M., & Gale, M. (2006). Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection. Proceedings of the National Academy of Sciences of the United States of America, 103(15), 6001-6006. https://doi.org/10.1073/pnas.0601523103